2-alkylideneamino-2h-1, 2, 4-benzothiadiazine 1, 1-dioxides and related compounds



United States Patent Peter H. L. Wei, Upper Darby, and Stanley C. Bell,

Philadelphia, Pa., assignors to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Filed Feb. 14, 1964,Ser. No. 344,830 Claims. (Cl. 260-443) This invention relates tocompositions of matter classified in the art of chemistry as substitutedbenzothiadiazines.

The invention sought to be patented in its principal composition aspectresides in the concept of a composition of matter being a chemicalcompound having a molecular structure in which there is attached to the2-position of the 2H-1,2,4-benzothiadiazine 1,1-dioxide nucleus anethylideneamino group or its hereinafter disclosed equivalents.

The tangible embodiments of the principal composition aspect of theinvention possess the inherent general physical properties of beingrelatively high melting crystalline solids; are substantially insolublein water and are soluble in polar solvents, such as lower aliphaticalcohols. EX- amination of the compounds produced according to thehereinafter described process reveals, upon spectrographic analysis,spectral data confirming the molecular structure hereinbefore set forth.The aforementioned physical characteristics taken together with thenature of the starting materials and the mode of synthesis positivelyconfirm the structure of the compositions sought to be patented.

The tangible embodiments of the principal composition aspect of theinvention possess the inherent applied use characteristic of exertingqualitatively varying therapeutic effects, as evidenced bypharmacological evaluation according to standard procedures. Thesetangible ernbodiments show central nervous system depressant effects.

The manner and process of making the invention will now be generallydescribed so as to enable a person skilled in the art of chemistry tomake the same.

The processes of the invention are illustrated schematicable forspecific embodiments thereof in Schemes A, C, and E, below, and moregenerally in Schemes B, C, and F, to which the numerals in parenthesisin the following description refer.

SCHEME A NH: Cl-

SOrNHNHz CH3 SCHEME B 3,314,950 Patented Apr. 18, 1967 ICC According toone procedure shown in Schemes A and B, the physical embodiments of thepresent inventive concepts are made by cyclizing with heat aphenylsulfonylhydrazide (1) (4) and an aldehyde to form aZ-alkylideneamino-3,4-dihydro-(2H)-1,2,4 benzothiadiazine 1,1 dioxide(3)(5).

According to a second procedure shown in Schemes C and D, the physicalembodiments of the present inventive concept are made by reacting aphenylsulfonylhydrazide (1)(4) with an alkylorthoacylate. This reactionJreferably is carried out by heating the reactants in a .ower alkanolsolvent, and the resultant products have 12-alkoxyalkylideneamino-ZH-1,2,4-benzothiadiazine 1,1- lioxide structure(6)(7).

According to a third precedure shown in Schemes E and F, the physicalembodiments of the present inventive :oncept are made by first reactinga phenylsulfonylhydraride (1) (4) with isatin to form an isatin,3-phenylsulfoniydrazone (8)(10). This reaction is preferably carried )utby heating the reactants in a lower alkanol solvent. The product soobtained then is cyclized in an inert solrent with phosgene to form a2-(3-indolinylideneamino)- ZH-1,2,4-benzothiadiazin-3 (4H)-one1,1-dioxide (9) (11). Equimolar amounts of reactants may be used butexcess Jhosgene is preferred.

The substituted 2-aminophenylsulfonyl hydrazides and :he isatin used inthe above-described process are generaly known or are readily preparedby procedures known those skilled in the art. However, a recommended:ynthesis for the former is given hereinbelow in Example l.

It will be apparent from the disclosure herein to those killed in theart of organic chemistry that for the purnoses of this invention,certain of the carbon atoms of the Z-amonophenylsulfonyl hydrazidesemployed as starting naterials can be substituted with non-interferinggroups. Fherefore, in the process of the invention, all 2-amino-Jhenylsulfonyl hydrazides can be employed in the process )f makingaspect of this invention to form compounds yhich are the fullequivalents of the invention as particilarly claimed. For example, butwithout limitation, :ither the 3,4, or the '5-position of theZ-aminophenyl- .ul-fonyl hydrazide starting compound (Formula I inchemes A, C, E) can be substituted with an alkyl group xuch as methyl,ethyl, propyl, isopropyl and hexyl, a halogen atom such as chlorine, ora bromine atom, a haloalkyl group such as trifluoromethyl anddichloromethyl, 1 nitro group, or an alkoxy group such as methoxy,ethixy, propoxy, butoxy, and pentoxy.

When the starting compounds are substituted as herenbefore reacted, itwill be apparent to those skilled in the Hi; that the final productsformed by the process of the nvention will bear, correspondingly, thesame substituznts. Such substituted compounds are the full equivaents ofthe invention as particularly claimed.

The best mode contemplated by the inventors of carryng out theirinvention will now be set forth as follows:

Example 1.6-chlore-3,7-dimethyZ-Z-ethylidcneamino-3,4-dihydr0-2H-1,2,4benzothiadiazine 1,1-di0xide A. Preparation ofstarting materiaL-Slowly add a di- )xane solution of 19.2 g. (.08 m.) of2-amino-4-chlo1'oi-methylbenzenesulfonyl chloride to a mixture of 30 g.f.5 m.) of an 85% hydrazine hydrate in water and diixane, with stirringand cooling. Add enough dioxane o dissolve all the solids. Store thesolution at room temerature overnight. Remove dioxane at reduced pres-.ure. Collect and wash the white solids with water. Re- :rystallize fromethanol to obtain a pure material meltng at 1346 C. with decomposition.

B. Preparation of final pr0dact.-Add to 6.0 g. (.0254 n.) of2-amino-4-chloro-5-methylbenzenesulfonylhydrazide, above prepared, in 50cc. of ethanol 3.4 g. (.075 m.) )f acetaldehyde. Treat the warm solutionwith Darco ind cool. Recrystallize to obtain a light yellow material romethanol (3.5 g.), M.P. 175177 C.

When tested pharmacologically according to standard :xperimentalprocedures this compound exhibited central lervous system depressantactivity.

The compositions constituting the invention can also be made accordingto the procedures hereinbefore set forth vherein substituents other thanthose hereinbefore enuaerated are added to the benzothiadiazine nucleus.The oxicity of and the asserted activity of the composition so nodifiedis not materially affected. Such additions to 4 the benzothiadiazinenucleus are illustrated as follows:

Substituents R and R in Formula 5, Scheme B, can be alkyl having from 1to 5 carbon atoms, haloalkyl of the same carbon content or phenyl orsubstituted phenyl. Substituent R in Formula 7, Scheme D, can behydrogen or an alkyl group having from one to five carbon atoms while Rcan be alkyl group having the previously indicated carbon content,

The 3-position (X) in Formula 11, Scheme F, can be substituted with anoxygen atom which may be converted to a sulfur atom, by heating withphosphorus pentasulfide. Substituents in the 2-position (Scheme F, R)can be an alkylidene group such as ethylidene and propylidene or analkoxyalkylidene group such as ethoxyethylidene, an

r arylalkylidene group, such as phenylethylidene, cyclohexylidene or anindolinylidene group.

Such additions to the molecular structure of the inventive conceptsherein described are fully equivalent to the subject matter particularlyclaimed.

The following examples illustrate the preparation of other compositionsof the invention.

Example2.-6-chlore-3,7-dimethyl-Z-ethoatyethylideneamin0-2H-1,2,4-benzothiadiazine1,1-di0xia'e Add 2-amino-4-chloro-5-methylphenylsulfonyl hydra- Zide (20g. or .085 m.), gradually to cc. of ethyl orthoacetate. Heat the mixtureand distill the ethanol formed from the reaction. Cool and collect 21 g.of crude product. Recrystallize the material from benzene, M.P. 171-4(dec.).

Example 3.--Isatin, 3-(2-amin0-4-chl0r0-5-methylphenyLsalfonylhydrazone) Heat a mixture of 14.7 g, (.1 m.) of isatin and anequal molar quantity of 2-amino-4-chlor0-5-methylphenylsulfonylhydrazinein ethanol on a steam bath for 10 min. Cool the mixture. Collect theyellow solids and wash with a small amount of ethanol. Recrystallize thecrude material from a mixture of dimethoxyethane and methanol, M.P.215-2l6 C.

Example 4.6-chl0r0 7methyl-2-(2-0x0-3-ind0linylidenamino)-2H-1,2,4-benz0rhiadiazin 3 (4H)one 1,1-di0xide Add a phosgene solution (1.5 g. or .0152 m.) indimethoxyethane to a solution of 3.65 g. (.01 m.) of isatin,3-(2-amino-4achloro 5 methylphenylsulfonylhydrazone), above prepared, inthe same solvent. Reflux the mixture for 5 /2 hours. Collect the yellowsolids and wash them with the same solvent to obtain a product weighing1.1 g., M.P. 235 (d).

It will be apparent that the compounds of our invention may be madeavailable in unit dosage forms, with the dosage adjusted for therespective activity of the particular compound, by admixing them withconventional excipients, extenders and the like.

Accordingly, the compounds of this invention can be adminstered withpharmaceutically acceptable inert carriers in a wide variety of oral orparenteral unit dosage forms containing 25, 100, 250 or 500 mg. of theactive ingredients, or in admixture with other active compounds.

The subject matter which the applicants regard as their invention isparticularly pointed out and distinctly claimed as follows:

1. A compound selected from the group consist g of those of the formulai u and wherein R is selected from the group consisting of hydrogen andalkoxy of less than six carbon atoms; R is selected from the groupconsisting of lower alkyl and phenyl lower alkyl, and together with thecarbon to which they are joined R and R is cyclohexylidene phenyl andindolinylidene; R is selected from the group consisting of hydrogen,alkyl of less than six carbon atoms and haloalkyl of less than sixcarbon atoms; R is selected from the group consisting of hydrogen, alkylof less than six carbon atoms, haloalkyl of less than six carbon atoms,and phenyl, and together R and R is oxo (0:); R is selected from thegroup consisting of hydrogen and alkyl of less than six carbon atoms; Xis selected from the group consisting of hydrogen, alkyl of less thansix carbon atoms, chloro, bromo, trifluoromethyl, dichloromethyl, nitroand alkoxy of less than six carbon atoms; and n is a positive integerless than four.

2. 6-chloro-3,7-dimethyl 2 ethoxyethylideneamino-2H-l,2,4-benzothiadiazine-l,l-dioxide,

3. 6-chloro 7 methyl-2-(2-oxo 3indolinylideneamino)-2H-1,2,4-benzothiadiazin-3 (4H)-0ne 1,1-dioxide.

4. 6-chloro-3,7-dirnethyl 2ethylideneamino-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide.

5. Isatin, 3-(2-amino-4-ch1oro 5 methylphenylsulfonylhydrazone)References Cited by the Examiner UNITED STATES PATENTS 3,163,644 12/1964De Stevens et a1. 260-443 NICHOLAS S. RIZZO, Primary Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA